Cincinnati Children's Hospital Medical Center (CCHMC) and Children's Hospital Boston (CHB) propose that the Pediatric Alliance for Genomic and Electronic Medical Record (EMR) Research (PAGER) becomes a site for the eMERGE Phase II network for pediatric institutions (RFA HG 11-022). We plan a sustained, scalable effort to inform and improve the care of the individual child using relevant genome and phenome wide association study (GWAS & PheWAS) data. The extraordinary faculty and informatics infrastructure of CCHMC & CHB has implemented center-wide healthcare tools to instrument the enterprise for genomic discovery based on the i2b2 (Informatics for Integrating Biology and the Bedside) platform. The PAGER i2b2 databases contain 2.5 million EMRs (all inpatient and outpatient visits) and grow by >100,000 new patients per year. The i2b2 data are uploaded from the Epic EMR and Cerner EMR, transformed, de-identified, augmented with research and legacy clinical data, and linked to the PAGER biorepositories and GWAS data. In addition, both institutions are in the process of implementing ambitious biorepositories that now contain >15,000 samples and will grow at >30,000 DNA specimens per year from children with i2b2 medical records. In Aim 1 we will build on our i2b2 infrastructure to develop SHRINE, which will allow phenotypic standardization and data sharing across eMERGE II. In Aim 2 we will contribute 6,861 cases that have EMRs, DNA, GWAS data, and institutional certification for submission to dbGaP, as well as a path to return results. Many colleagues in the academic faculties at both CHB and CCHMC are advocates for phenotypes of their scholarly interest, providing a multitude of possibilities for phenotype algorithm development and application of GWAS and PheWAS for the eMERGE II network. We will contribute to and explore the previous and new phenotypes selected by the eMERGE II Steering Committee. In Aims 3 and 4 we will explore the attitudes towards, and use of, clinically relevant and incidental genomic findings in patient and control groups. We will utilize the infrastructure of our novel Informed Cohort Oversight Board (ICOB), implemented for The Gene Partnership (TGP), to develop a national process to address the ethical issues surrounding the return of research results to parents, participants, and caregivers. We hope to contribute significantly toward a consensus for standard procedures that fulfill patient expectations and needs, and that improve patient care. Finally, the two PAGER institutions plan major investments in the infrastructure supporting eMERGE II, valued at >$50,000,000 in aggregate over the next five years, which will greatly enhance the productivity of the PAGER site and eMERGE II. Our great interest in joining eMERGE II derives from its anticipated contributions toward the missions of CCHMC and CHB, which are to improve child health and transform delivery of care through fully integrated, globally recognized research, education, and innovation. PUBLIC HEALTH RELEVANCE: We will combine the resources, energies, and scholarly commitment of two leading children's hospitals to apply the extraordinary technologies of the electronic medical record, high-throughput genotyping, and biological specimen preservation to use genomics to advance understanding and therapy of illnesses that afflict children. Concurrently, we will also address the many privacy, ethical, educational, and inter-institutional exchange issues raised by these new capabilities in an effort to find wide-spread acceptance of methods and procedures that will allow the new capabilities to be effectively and beneficially incorporated into routine clinical care.